We report a case of compound heterozygous hemoglobins S [beta6(A3)Glu6Val] and Korle-Bu [beta73(E17)Asp73Asn] in a 2-year-old girl. This hemoglobin genotype is associated with a benign clinical course, much like the sickle cell trait; however, its laboratory characteristics are very similar to compound heterozygous hemoglobin S and hemoglobin D-Los Angeles [beta121(GH4)Glu121Gln], which produces severe sickling hemolytic anemia. We describe laboratory data used to resolve this important differential diagnosis and review the interactions between hemoglobin S and the variant hemoglobins that may account for the different clinical phenotypes in compound heterozygotes.